Physical inactivity and skeletal muscle disuse are a risk factor for cardiovascular disease (CVD), the most prevalent health problem and a leading cause of death in the US. Skeletal muscle inactivity is widely present in various chronic diseases and injuries, obesity, aging, and sedentary life style and leads to capillary regression, which contribute to muscle wasting, hypertension, and insulin resistance. A critical barrier to the effective prevention and treatment of muscle inactivity-induced capillary regression is the poor understanding of the underlying mechanisms. Brain derived neurotrophic factor (BDNF) was originally found in the brain but now recognized to be also produced in skeletal muscle as a myokine. Our recent data showed that inactive muscles had increased pro-BDNF and reduced mature-BDNF release. We further observed that pro-BDNF induced endothelial cell apoptosis, which was mitigated by mature-BDNF. This study will test a central hypothesis that increased pro-BDNF and decreased mature BDNF release from inactive skeletal muscles, due to the impaired BDNF cleavage, play a critical role in capillary regression. Three specific aims will be pursued to (1) define the role of muscle derived pro-BDNF in capillary regression; (2) determine the role of muscle mature-BDNF in capillary regression; and (3) delineate the aberrant BDNF cleavage as an underlying mechanism of the abnormal pro- and mature-BDNF release from the inactive muscles. Based on these investigations, we will test whether blockade of pro-BDNF receptor pathway, stimulation of mature BDNF receptor pathway, or enhancement of BDNF cleavage function would be potential therapeutic approaches to prevent and treat muscle inactivity-induced capillary regression to lower the risk for CVD.